PMID- 33630975
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20220323
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 17
IP  - 2
DP  - 2021 Feb
TI  - Super enhancer-mediated transcription of miR146a-5p drives M2 polarization during 
      Leishmania donovani infection.
PG  - e1009343
LID - 10.1371/journal.ppat.1009343 [doi]
LID - e1009343
AB  - The outcome of Leishmania donovani infection depends upon the dynamic 
      interchanges between M1 and M2 macrophages. Information of the involvement of 
      microRNAs (miRNAs) and epigenetic modifiers in regulating macrophage plasticity 
      during L. donovani infection is still elusive. Differential expression analysis 
      of polarization-regulating miRNAs, revealed significant enrichment of miR146a-5p 
      during Leishmania donovani infection. A sustained enrichment of miR146a-5p was 
      observed in both infected bone marrow derived macrophages (BMDMs) and BALB/c mice 
      organs. We found involvement of miR146a-5p in phagocytosis and survivability of 
      parasites. Moreover, miR146a-5pgot enriched in interleukin 4- stimulated BMDMs, 
      indicating its possible involvement in M2 polarization. Upon transfecting BMDMs 
      with miRVANA anti-146a oligos, M2 markers (CCR7, YM-1, FIZZ-1, arginase-1, IL10 
      and IL4) and transcription factors (p-STAT6 and c/EBPbeta) got depleted with 
      concomitant augmentation of M1-polarizing transcription factors (p-STAT1, AP1 and 
      IRF-1), miR146a target genes (TRAF6 and IRAK1), M1 cytokines (IL12 and TNFalpha), 
      iNOS, nitric oxide, and nuclear translocation of phospho p-65 subunit. 
      Neutralization of intracellular mature miR146a-5p pool in infected BALB/c mice 
      lower organ parasite burden and expressions of M2 markers and IL10 with 
      enrichment of M1 markers like iNOS and IL12. Additionally, we explored the novel 
      role of super enhancer (SE), a cis-acting regulatory component, to enrich 
      miR146a-5p expression during infection. Enhanced expression and nuclear retention 
      of SE components like BET bromodomain 4 (BRD4) and p300 were found in infected 
      BMDMs. Upon silencing BRD4, expressions of miR146a-5p and M2 markers were down 
      regulated and TRAF6, IRAK1 and iNOS levels increased. STRING V.11 based 
      predication and immune precipitation confirmed the strong interaction amongst 
      BRD4, p300 and RNA pol II (RpbI). Chromatin immune precipitation studies 
      suggested the recruitment of BRD4 at the enhancer loci of miR146a-5p gene during 
      infection. Altogether, our findings revealed a novel role of BRD4/p300-depdendent 
      super-enhancer in regulating miR146a expression during L. donovani infection 
      which in turn mediates M2 polarization and immune-suppression.
FAU - Das, Sonali
AU  - Das S
AD  - Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical 
      Biology, Kolkata, India.
FAU - Mukherjee, Sohitri
AU  - Mukherjee S
AD  - Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical 
      Biology, Kolkata, India.
FAU - Ali, Nahid
AU  - Ali N
AUID- ORCID: 0000-0002-6166-3778
AD  - Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical 
      Biology, Kolkata, India.
LA  - eng
GR  - MR/P027989/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210225
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn146 microRNA, mouse)
RN  - 0 (STAT6 Transcription Factor)
RN  - 0 (Stat6 protein, mouse)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases)
RN  - EC 2.7.11.1 (Irak1 protein, mouse)
SB  - IM
MH  - Animals
MH  - *Enhancer Elements, Genetic
MH  - Interleukin-1 Receptor-Associated Kinases/genetics/metabolism
MH  - Leishmania donovani/*physiology
MH  - Leishmaniasis/genetics/*immunology/metabolism/parasitology
MH  - Macrophages/*immunology/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - MicroRNAs/*genetics
MH  - Nitric Oxide Synthase Type II/genetics/metabolism
MH  - *Phagocytosis
MH  - STAT6 Transcription Factor/genetics/metabolism
PMC - PMC7943006
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/02/26 06:00
MHDA- 2021/06/24 06:00
PMCR- 2021/02/25
CRDT- 2021/02/25 17:17
PHST- 2020/09/11 00:00 [received]
PHST- 2021/01/28 00:00 [accepted]
PHST- 2021/03/09 00:00 [revised]
PHST- 2021/02/26 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2021/02/25 17:17 [entrez]
PHST- 2021/02/25 00:00 [pmc-release]
AID - PPATHOGENS-D-20-02024 [pii]
AID - 10.1371/journal.ppat.1009343 [doi]
PST - epublish
SO  - PLoS Pathog. 2021 Feb 25;17(2):e1009343. doi: 10.1371/journal.ppat.1009343. 
      eCollection 2021 Feb.